[unreadable] This Mentored Clinical Scientist Development Award proposal describes a 5-year program to promote the successful development of an independently-funded translational researcher in Hematology. The principal investigator has completed his clinical training in Internal Medicine and Hematology/Medical Oncology at the Mayo Clinic College of Medicine and now seeks to bring his skills and expertise to bear on the role of oxidative stress in the pathogenesis of systemic amyloidosis. This project builds on the candidate's prior experience in basic research in hereditary amyloidosis, which he earned his doctorate studying at Indiana University. It also exploits the expertise of the Mayo Clinic in the clinical diagnosis and treatment of systemic amyloidosis. [unreadable] The sponsor of this project, Dr. Karl Nath, is a member of the Division of Nephrology at the Mayo Clinic College of Medicine and a recognized leader in the field of oxidative injury. Dr. Nath described the importance of HO-1 in protection from oxidative stress over a decade ago and has published extensively on the involvement of HO-1 in mediating the toxicity of a wide variety of noxious stimuli. He was awarded a MERIT award last year for his contribution in this area. Dr. John Lust is also participating as a co-mentor and by providing laboratory space and equipment. Dr. Lust is a consultant in Hematology at the Mayo Clinic and has been actively involved in discerning the role of various cytokines, especially interleukin-1, in the pathogenesis of multiple myeloma. His laboratory and clinical expertise will greatly enhance this project. [unreadable] This project will focus on establishing the role of oxidative stress in the formation and toxicity of systemic amyloidosis. The specific aims include: 1) Examining the effect of amyloidogenic proteins on renal epithelial cells in vitro, 2) Comparing the extent of oxidative stress, amyloid burden and end-organ damage in two experimental animal models: one susceptible to systemic amyloidosis and the second resistant to amyloidosis, and 3) Testing the hypothesis that animals deficient in HO-1 will show greater amounts of oxidative stress, increased amyloid deposits and more end-organ damage and whether exogenous anti-oxidant therapy will provide a protective effect. [unreadable] This work will examine different pathways of toxicity to identify potential targets for therapeutic intervention, which can be tested in the in vitro and in vivo models described above. Information learned in these studies will then be applied in translational clinical studies exploring the efficacy of these agents in reducing or preventing the toxicity of amyloid deposits in patients with this fatal illness [unreadable] [unreadable]